Novel 1-methyl-1, 3, 5(10), 9(11)-estratetraenes and methods for their manufacture



United States Patent Oti 3,082,225 Patented Mar. 19, 1963 ice 3,082,225NGVEL l-ltdE'lHYL-l,3,5(l0),9(1l)-ETRATETRA- ENES AND METHODS FOR THEXRMANU- FACTURE Hans Reimann, Bloomfield, N.J., assignor to SeheringCorporation, Bloomfield, Null, a corporation of New Jersey No Drawing.Filed Sept. 15, 1961, Ser. No. 138,270 13 Claims. (Cl. 260-39145) CH3AI/ J H wherein R is selected from the group consisting of hydrogen,lower alkyl, lower alkanoyl, Z is selected from the group consisting of:

with R representing a substituent selected from the group consisting ofhydrogen and lower alkanoyl, and R" representing a substituent selectedfrom the group consisting of lower alkyl and ethinyl.

In addition to the foregoing estratrienes, l-methyl-9(ll)-dehydroestrone and the 3-lower alkyl ethers and 3- esterderivatives thereof may be prepared by the novel process of myinvention.

The above definition of the novel compounds prepared by my new method ofderivation should not be strictly construed, but rather may beconsidered to admit the presence of other substituents on the steroidnucleus particularly at positions 6 and 16 such as the 6rx-methyl,6afluoro, 6ot-chloro, l-6ot-hydroxy, l6a-acyloxy, l6-methyl and16-halogen analogs thereof. This modification depends solely on thechoice of starting material which may possess the desired substituentsin the positions incated.

The terms lower alkyl and lower alkanoyl as they appear above representthose substituents having from 1 to 6 carbon atoms therein, such asmethyl, ethyl, propyl, 'butyl, and formyl, acetyl, butyryl, propionyland the like, respectively.

The lower alkyl radicals represented by R are exemplified by methyl,ethyl, propyl, butyl, pentyl, hexyl, and the branched chain isomersthereof. Some examples of lower alkanoyl radicals as designated by R areformyl, acetyl, propionyl, butyryl, valeryl, caproyl, and the branchedchain isomers thereof, said groups being the acyl radicals of alkanoicacids containing up to 6 carbon atoms. Halogen as employed herein hasits conventional scope to embrace chlorine, bromine, fluorine andiodine.

In general to carry out the novel process of my invention a steroidal3-keto-l,4,9 (l'l)-triene of the androstane or pregnane series istreated with a strong acid catalyst having a dissociation constant equalto or greater than 2 'l0 exemplified by acids such as p-toluenesulfonicacid, and trifluoroacetic acid, in a solvent, preferably a loweralkanoic acid or acid anhydride, at a temperature in the range of about20-100 C. for a period extending anywhere from one half to 72 hours. Thereaction time Will depend on the temperature of the reaction maintained,the particular activity of the catalyst employed, and the nature of thespecific steroid converted. The product recovered will be found toconsist of a l-methylated-1,3,5(1'0),9( l l)- estratetraene such as areillustrated above.

The starting materials for our process are in general known3-keto-1,4,9(11)-pregnatrienes or 3-keto-1,4,9(11)- androstatrieneswhich include, for instance, 1,4,9(l'1)- androstatriene-B,l7-dione,1,4,9 (11) androstatriene-l7fiol-3-one, l,4-,9 (l1)-pregnatriene-l7ot-ol-3,20-dione, 1,4,9- 1-1)-pregnatriene-3,-20-dione,1,4,'9*( l 1 )-pregnatriene-17a, 2l-diol-3,20-dione 21-acetate, and thelike. These starting materials may also be substituted in the nucleus orin the side chain, for example in the 6 and/ or 16 position, by halogenoor lower alkyl groups, hydroxy or acyloxy groups such as6a-iluoro-1,4,9(ll)-androstatriene-3,l7-dione, 6a-fl-uoro-1,4,'9( l 1)pregnatriene "t,21-dlO1-3,20- dione,6a-methyl-l,4,9-'(1l)-androstatriene-3,17-dione and ot-methyl l,4,9('11)-pregnatriene 17a-21-diol-3,20-dione disclosed in copendingapplication Serial No. 817,071, filed June 1, 1959, now Patent No.3,032,664 and the known l-6-methyl substituted l,4,'9*(1 l)-trienes suchas 16a-methy1 1,4,9(11)- regnatriene 17a,2l-diol 3,20-dione,16amethyl-1,4,9( l l )-androstatriene-3,17-dione, 16cc methyl- 1,4,9(ll)androstatriene 17p ol 3-one, and other 16- chloro-, l6-fluoro-,l6-hydroxy-, and l 6-acyloxysubstituted 1,4,9 ('l l)-androstatriene 3,17diones and pregnatriene-3,20-diones well known in the art.

For instance, a suitable starting material selected from the above forthe manufacture of our novel compounds is 1,4,9(1l)-pregnatriene-l7a-ol-3,20-dione. Illustratively, the reaction of thiscompound with trifluoroacetic anhydride in acetic acid accompanied byheating results in the formation of l-methyl acetyl-l,3,5(l0),9(1l)-estratetraene 3,1704 diol diacetate l-methyl-l9-nor-1,3,5(10),9(1l)-pregnatetraene-3,l7a-diol-20-one diacetate). Furthertreatment of this ester with a reagent such as methanolic potassiumhydroxide gives the corresponding 3,17-diol. Alternatively, treatment ofthe 3,17-diacetate with perchloric acid in methanol will hydrolyze theester group on the 3-carbon to a hydroxy group yielding another of thenovel compounds of this invention, i.e., 1-methyl-175-acety1-l,3,5(l0),9( 11) estratetraene-3,171 diol l7-acetate (l-methyl-19-nor-1,3,5(l0) ,9 1 l )-pregnatetraene-3,l7cx-diol-20-one l7-acetate). This latterproduct may, in turn, be treated with a reagent such as benzoyl chloridein pyridine to give the corresponding 3-benzoate ester, i.e.,l-methyl-l7,B-acetyl-1,3,5(l0),9(11)-estratetraene-3,l7a-diol 17-acetate3-benzoate (1-methyl-19-nor- 1,3,5(10),9(ll)preguatetraene-3,l7u-diol-20-one 3-ber1- zoate l7-acetate).

Suitable catalyst-solvent combinations are, for example, trifiuoroaceticanhydride-acetie acid, p-toluenesulfonic acid-acetic acid, and the like.Other suitable acid catalysts include benzenesultonic acid, andanhydrous hydrochloric and sulfuric acids, while solvents may includesuch as propionic acid, propionic anhydride, butyric acid, and the like.These are selected at random and it is to be realized that othervariations in catalysts and solvents will readily occur to those skilledin the art. In the case of trifluoroacetic anhydride, it should be notedthat this anhydride should be employed with a carboxylic acid so a as toset up an equilibrium whereby trifluoroacetic acid is generated in situin the system.

It has heretofore been unknown to subject a 3-keto- 1,4,9(l1)-trienesteroid to an acid-catalyzed rearrangement medium such as is disclosedherein. Furthermore, it is unexpected, under the anhydrous conditions ofmy process, that a l-methyl-3-hydroxy-aromatic-A-ring steroid isobtained from the 3keto-1,4,9(ll)-triene starting com pounds of myprocess. Heretofore, c-ringunsubstituted- 3-keto-1,4-dienes devoid of aconjugated double bond at C-6 (e.g., 1,4-androstadiene-3,17-dione) whensubjected to anhydrous, strong acid conditions similar to those of myprocess, would convert to a 1-hydroxy-4-methyl steroid (e.g., to1-hydroxy4-methyl 1,3,5 estratriene 17- one). By my process, on theother hand, steroids devoid of conjugated double bonds and unsubstitutedin the C- ring, e.g., 3-keto-1,4,9(l1)-trienes such asl,4,9(11)-pregn'atriene 3,20 dione and 1,4,9( 1 l )-androstatriene-3,l7-dione, are catalytically rearranged in an anhydrous, strong acid mediumto the corresponding 1-methyl-3-hydroxy- 17 8-acetyl-1,3,5(10),9(11)estratetraene (i.e., 1-methyl- 3-hydroxy-l9 nor 1,3,5(10),9(ll)pregnatetraene-ZO- one) and 1-methyl-9(l1)-dehydroestrone (i.e.,l-methyl- 1,3,5 10) ,9( 1 1 -estratetraene-3-oll7-one) respectively.

As a general rule, when an anhydride is employed in my process, thecorresponding ester of the phenolic hydroxyl at the 3-carbon is obtainedand any other hydroxyl groups in the molecule are also esterified. Onthe other hand, when an acid is used as the solvent, the correspondingfree phenol may be obtained.

By my novel process as described herein, 1,4,9(11)-androstatriene-B-one-175-01 and 16a methyl 1,4,9(11)-androstatriene-3-One-l'ifi-ol upon reaction with p-toluenesulfonic acidin acetic acid yields respectively l-methyl- 9(11) dehydroestradiol andl,16a-dimethyl-9(11)-dehydroestradiol. Alternatively, the1-met'nyl-9(11)-dehydroestradiols of my invention may be derived byutilizing known techniques from 1-methyl-9(11)-dehydroestrone which, inturn, is obtained by the process of this invention by the action ofp-toluenesulfonic acid in acetic acid on1,4,9(11)-androstatriene-3,17-dione. Thus, for example, reduction of1-methyl-9(11)-dehydroestrone with sodium borohydride yields1-methyl-9(11)-dehydroestradiol which may, if desired, be transformed byconventional methods such as with acetic anhydride in pyridine to itsester derivatives. Additionally, the 17-keto group of l-methyl-9(11)del1ydroestrone may be treated with an alkyl Grignard reagent suchas methyl magnesium iodide to give the corresponding 17u-methyl- 17phydroxy compound, 1,17a dimethyl 9(11) dehydroestradiol. Similarly, 1-methyl-9(1l)-dehydroestrone upon reaction with sodium acetylideaccording to known techniques yields the corresponding 17u-ethinyl17fl-hydroxysteroid, 1-methyl-17 zethinyl-9(11)-dehydroestradiol. Ifdesired, the phenolic 3-hydroxy group in the estratetraenes prepared bymy process may be esterified in the usual manner, or converted to anether function, for example 3-methoxy, by means of dimethyl sulfate andbase.

The 1,3,5 (10),9(1l)-estratetraenes of my invention are valuable asintermediates in the synthesis of therapeutically valuable9,11-disubstituted-1-methyl-aromatic-A-ring steroids such as aredescribed in co-pending application of Reimann and Robinson, Serial No.138,271 filed on even date with the instant application. The9(11)-double bond of the estratetraenes of this invention may beutilized in the synthesis of 9,11-disubstituted-l-methyl-estrogens ofReimann et al. by addition of halogens or hypohalous acids and the like,to yield 9,11-dihalogenated compounds or 9,11-halohydriris and estersthereof.

In addition to their use as intermediates the novel compounds of thisinvention show useful estrogen-like activity, such as the ability tolower serum cholesterol while exhibiting greatly reduced, undesirableestrogenic sideeftects. On the other hand, the novel derivatives pro-EXAMPLE 1 1-Methyl-1,3,5(10) ,9(1 1 )-Estratetraene-3-0l-17-0ne (A) To asolution of 1.0 g. of 1,4,9(11)-androstatriene-3,17-dione in 40 ml. ofacetic anhydride is added 250 mg. of p-toluene-sulfonic acid. Themixture is flushed with argon and heated on the steam bath for 5 hours,then poured into ice-water and stirred to hydrolyze any excessanhydride. The resulting product containing 1-methyl-- 1,3,5 (l0),9(11)-estratetraene-3-ol-17-0ne acetate, is dis solved in 20 of methanol,then a solution of 1 g. of potassium hydroxide in 2 ml. of water isadded and the mixture heated under reflux for 20 minutes. The solution:is poured into ice-water and acidified with hydrochloric acid. Theresulting precipitate is filtered, washed with water, dried,crystallized from ether-hexane and recrystal-- lization from ether togive 1methyl-1,3,5( 10),9(l1)- estratetraene-3-ol-17-one M.P. 163165 C;

nton 215 mu 24,100), 253 my (6 12,100)

mux.

[a] +245 C. (CHCl This compound is soluble in dilute aqueous base. i

(B) To a solution of 1.0 g. of 1,4,9(1l)-androstatriene- 3,17-dione in40 m1. acetic acid is added 250 mg. of ptoluenesulfonic acid. Themixture is heated on the steam bath for 5 hours, then poured intoice-water. The resulting precipitate is filtered, dried, andcrystallized twice from ether-hexane to give 1-methyl-1,3,5(10),9(11)-estratetraene-3-ol-17-one (i.e., 1-methyl-9(11)-dehydr0- estrone).

EXAMPLE 2 1 -M ethyl estrone A 214 m (6 10,400), 282, e

max.

The infrared spectrum is identical with that of an authentic 1 sample.

EXAMPLE 3 1-Me1hyl-1,3,5(10),9(11)-Estratetraene-3-Ol-17-0112 Acetate Toa solution of 250 mg. of 1-methyl-1,3,5(l0),9(1l)-estratetraene-3-ol-17-one in 5 ml. of pyridine is added 1 ml. of aceticanhydride. The mixture is allowed to stand at room temperature for 22hours, then is poured into ice-water and stirred to hydrolyze any excessanhydride. A solid separates which is crystallized from ether to give1-methyl-1,3,5(10)-estratetraene-3-ol-17-one acetate, M.P. 126 C.;

A3152 212 me (6 27,000), 247 me (6 13,300)

[cc] +215 (CI-1G 5 EXAMPLE 4 1-Methyl-1,3,5(10),9(11-Estratetraene-3-Ol-17-One Methyl Ether To a solution of 500 mg. of1-methyl-1,3,5(10),9(11)- 5 estratetraene-3-ol-17-one in 25 ml. methanolis added a solution of 3 g. potassium hydroxide in 5 ml. of water. Themixture is chilled and 2 ml. of dimethyl sulfate is added dropwise, thenthe mixture is stirred at room temperature for /2 hour. Additional 2 ml.portions of dimethyl sulfate are added at the next two /2 hourintervals, then the mixture is stirred a final /2 hour, and allowed toevaporate overnight. with Water, dried, crystallized twice fromether-hexane to give 1-methyl-1,3,5(10),9(11) estratetraene-S-ol-l7-onemethyl ether, M.P. 100-102 C.; I

MBOH 213 me (6 31,300), 252 my (6 17,300)

max.

[0611) -l-'262 EXAMPLE 5 l-Metlzyl-I7a-Ethinyl-1,3,5 (10) ,9 (1]-Estratetraene- 3,1 7 ,8-D iol ALSQ 214, 253 m EXAMPLE 6 1 -Methyl-1,3,5(10) ,9 (11 -Estratetraene-3,17,8-Diol A solution of 2.5 g. of1-methyl-l,3,5(l0),9(l1)-estratetraene-3-ol-17-one in 50 ml. of methanolis chilled in ice. To the chilled solution 2.5 g. of sodium borohydrideis added in portions and the resulting solution kept at C. until foamingsubsides. The reaction mixture is then allowed to stand at roomtemperature for 1 hour, acidified with hydrochloric acid and dilutedwith water. The resulting precipitate is filtered and crystallized fromaqueous acetone to give1-methyl-1,3,5(10),9(11)-estratetraene-3,l7,B-diol, M.P. 148-152 0.;

my 215 m (6 25,000), 253 me ((-1 13,200) [OC]D -l138 EXAMPLE 71-Methyl-1,3,5(10),9(11)-Estratetraene-3,17,8-Di0l Diacetate (A) Asolution of 1.5 g. of the l-methylestratetraene of Example 6 in 15 ml.of pyridine and 2 ml. of acetic anhydride is allowed to stand at roomtemperature for 18 hours. The solution is then poured into ice-water andthe resulting precipitate is filtered, dried, and crystallized twicefrom ether-hexane to give 1-methyl-1,3,5(10),9(11)-estratetraene-3,17B-diol diacetate, M.P. 128-129 C.; [LX113 {-78 (B) Toa solution of 1.0 g. of 1,4,9(1l)-androstatriene-17fl-ol-3-one in 40 ml.of acetic anhydride is added 250 mg. of p-toluenesulfonic acid. Theflask is flushed with argon and the mixture is heated on the steam-bathfor 5 hours, then poured into ice-water, and stirred for V2 hour tohydrolyze any excess anhydride. The resulting precipitate is filtered,washed with water, dried, and crystallized from ether-hexane to give1-methyl-1,3,5(10), 9(11)-estratetraene-3,17;8-diol diacetate.

The resultant residue is washed hours, then poured into ice-water.

6 EXAMPLE 8 1-Methyl-1,3,5 (10) ,9 (11 -Estratetraene-3,I 713-Di0lDipropionate To a solution of 500 mg. of 1,4,9(l1)-androstatrienel7fl-ol-3-one in 20 ml. of propionic anhydride is added 125 mg. ofp-toluenesulfonic acid. The mixture is reacted and the resulting productisolated in a manner similar to the procedure of Example 7B. The productis then crystallized from ether-hexane to give 1-methyl-1,3,5( l0), 9 11 -estratetraene-3,17B-diol dipropionate.

EXAMPLE 9 1 Methyl 17,8 Acetyl 1,3,5(10),9(11) Estratetraale-3,] 7a-Diol Diacetate (1-Methyl-J9-N0r-1,3,5 (10) 9 (11 -Pregnatetraene-3,1 7a-Di0l-2 O-One Diacetate) A solution of 1.0 g. of1,4,9(1l)-pregnatriene-l7a-ol- 3,20-dione in 10 ml. of acetic acid and 2ml. of trifluoroacetic anhydride is flushed with argon and heated on thesteam-bath for 50 minutes. The solution is then cooled and poured intoice-Water. The resulting precipitate is filtered, dried, dissolved inether and filtered through a short Florisil column. The eluted oil istriturated with ether-pentane to give a solid which is crystallized fromether-hexane to give 1-methyl-17 3-acetyl-l,3,5 (10),9( ll)-estratetraene-3,17a-diol diacetate, M.P. 143-146 C.;

mg 211 m l (6 27,000), 248 my (6 13,800) [a] f+84 (CHCl EXAMPLE l0 1Methyl 17 3 Acetyl ],3,5(10),9(I1) Estratetraate-3,1 7 a-Diol 17-Acetate(1-Methyl-19-N0r-1,3,5 (10), 9 (11 -Pregnatetraene-3,17ot-Di0l-20-0ne J7 -A cetate) To a solution of 530 mg. of l-methyl-17/3-acetyl-1,3,5(l0),9(ll)-estratetraene-3,l7ot-diol diacetate in 25 ml. of methanol isadded 0.53 ml. of 70% perchloric acid and the mixture allowed to standat room temperature for 18 The resulting precipitate is filtered, driedand chromatographed on Florisil. Suitable fractions, as determined bypaper chromatography, are combined and crystallized from ether-hexaneand ether-acetone to give 1-methyl-17;8-acetyl-1,3,5(l0),

9(11)-estratetraene-3,l7ot-diol 17-acetate, M.P. 227-235.

AMeOH mm 215 my (6 24,000), 252 m,u (6 12,300) [ot] '+l10 (CHClg).

EXAMPLE l1 1 Methyl 17B Acetyl 1,3,5(10),9(I1) Estratetraene-3,17u-Di0l(J-Methyl-19 Nor 1,3,5(10),9(11)- Pregnatetraene-3,J 7 a-D i0l-20-One) Asolution of mg. of the 3,17-diacetate of Example 9 in 4.5 ml. of 5%potassium hydroxide in methanol and 0.5 ml. of Water is heated underreflux for 15 minutes. It is then acidified with dilute hydrochloricacid and poured into water. The resultant precipitate is filtered andcrystallized twice from ether-hexane -to give l-methyl-17,6-acetyl-1,3,5(10),9(l1)-estratetraene-3,17ot-diol, M.P. 197-205 C-my 215 my (6 27,800), 254. my (a 13,900) [06113 +86 ('CHClg).

Alternatively, the 17-monoacetate compound of Example 10 is hydrolyzedaccording to the above procedure to give the desired from the diacetateas above.

EXAMPLE 12 I Methyl 17;? Acetyl 1,3,5 (10) ,9 (1]) Estratetraene-3-Ol(1-Methyl-19-N0r-I,3,5(10) ,9 (1] -Pregnatetraene-3-0l-20-One) A sampleof 500 mg. of 1,49(11)-pregnatriene-3,20- drone is allowed to react withacetic anhydride and pproduct, identical with that preparedtoluene-sulfonic acid according to the procedure of Example 1A and theproduct hydrolyzed and isolated as described, then crystallized twicefrom ether-hexane to give1-methyl-17fl-acetyl-1,3,5(10),9(11)-estratetraene-3- o1,

m 215 ma (6 25,200), 253 mg (6 12,000) [0.] +204 (CHCl EXAMPLE 13 1Methyl 17/3( 3' Acetoxyacetyl) 1,3,5(),9(11)-Estratetraene-3,17a-Di0l-20-One Diacetate (I-Methyl- 19 Nor1,3,5(10),9(11) Pregnatetraene 3,17u,21- Tri0l-20-0ne Triacetate Five g.of 1,4,9(11)-pregnatriene'17u,21-diol-3,20-dione 21-acetate is allowedto react with acetic anhydride and p-toluenesulfonic acid according tothe procedure of Example 7B to give 1methyl-17B(;8-acetoxyacetyl)-1,3,5(10) ,9( 1 1 -estratetraene-3, 17oc-diol-20-one diacetate M552 213 m (623,300), 247 Inn (6 10,300)

EXAMPLE l4 1 -Methyl-1 7/3-Acetyl-1,3,5(10),9(1 1 )-Estratetraene- 3,17a-Di0l 3-Benz0ate 1 7-Acetate EXAMPLE 1,1 7ot-Dimethyl-1,3,5 (1 0) ,9(11 -Estratetraene-3,1 7 ,8-D iol To a solution of 1 gram of1-methyl-1,3,5(10),9(11)- estratetraene-3-ol-17-one (the compound ofExample 1) in 50 ml. of tetrahydrofuran is added dropwise with stirringto an ethereal solution of methyl magnesium iodide (prepared from 3grams of magnesium metal and 7.5 ml. of methyl iodide in 200 ml. ofanhydrous ether). The reaction mixture is diluted with 150 ml. oftetrahydrofuran then distilled until 200 ml. of distillate has beencollected. The reaction mixture is then refluxed for 1 hour, cooled andpoured slowly into 200 m1. of cold 10% aqueous ammonium sulfatesolution. The mixture is extracted with methylene chloride and theorganic extracts are combined, washed with water, and concentrated to aresidue which is crystallized. from acetonehexane to give1,17a-dimethy1-1,3,5(10),9(11)-estratetraene-3,17fl-diol.

By substituting other Grignard reagents, such as ethyl magnesium bromidefor methyl magnesium iodide in the above procedure, there is obtainedthe corresponding 17aalkyl derivative, e.g.,1-methyl-17u-ethyl-1,3,5(10),9(11)- estratetraene-3,17fi-diol.

EXAMPLE 16 1,16ot-Dimethyl-1,3,5(10),9 (11 )-Estratetraene-3,17fi-Di0l(1 16d'Dl-mthyl'9 (1 1 -Delzy droestradiol)16a-Methy1-1,4,9(11)-androstatriene-17,6-ol-3-one is reacted withp-toluenesulfonic acid in acetic acid in the manner described in Example1B. The resultant product is isolated as described to give1,16a-dimethy1-1,3,5(l0), 9(11)-estratetraene-3,17,6-dio1.

I claim:

1. A process for the production of I-methyl-hydroxy-1,3,5(10),9(11)-estratetraenes which comprises heating a3-keto-1,4,9(11)-triene taken from the group consisting of3-keto-1,4,9(11)-androstatrienes and 3-keto-1,4,9(l1)- pregnatrieneswith a-strong acid catalyst .in a solvent of the group consisting ofcarboxylic acids and carboxylic acid anhydrides.

2. A process according to claim 1 wherein the strong acid catalyst isp-toluenesulfonic acid and the solvent is acetic anhydride.

3. A process according to claim 1 wherein the strong acid catalyst isp-toluenesulfonic acid and the solvent is acetic acid.

4. A process according to claim 1 wherein the strong acid catalyst istrifiuoroacetic anhydride and the solvent is acetic acid.

5. In the process for the production of compounds having the followingstructural formula:

tr CH3 Ml wherein R is selected from the group consisting of hydrogen,lower alkyl and lower alkanoyl; Z is selected from the group consistingof:

R being selected from the group consisting of hydrogen and loweralkanoyl', R being selected from the group consisting of lower alkyl andethinyl; the step which comprises heating a compound of the formula:

on, CH3

wherein Z is as defined above, with a strong acid catalyst in a solventof the group consisting of carboxylic acids and carboxylic acidanhydrides.

6. A compound of the structural formula:

wherein R is selected from the group consisting of hydrogen, loweralkyland lower alkanoyl; Z is selected from the group consisting of:

R being selected from the group consisting of hydrogen and loweralkanoyl; R being selected from the group consisting of lower alkyl andethinyl.

7. 1 methyl 17a ethinyl 1,3,5(10),9(11)-estratetraene-3,17B-diol.

8. 1,170; dimethyl 1,3,5(10),9(1l) estratetracne- 3,17i3-diol.

9. 1 methyl acetyl 1,3,5(10),9(11) estratetraene-3,17 x-diol diacetate.

References Cited in the file of this patent Elks et al.: Proceeding ofthe Chemical Society, January 1959, pp. 6 and 7 Mills et al.: J.A.C.S.82 5882-5889 (Nov. 20, 1960) (p. 5883 depended upon).

Kirk 61: 211.: ].C.S. (1960), pp. 46644667.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,082,225 March 19, 1963 Hans Reimann It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column 7, line 71 for "lmethylhydr0xy" read lmethyl-3hydroxy Signed andsealed this 8th day of October 1963.

(SEAL) Attest:

EDWIN L. REYNOLDS ERNEST W. SWIDER Attesting Officer AC t i 11 Q5Commissioner of Patents

6. A COMPOUND OF THE STRUCTURAL FORMULA: 